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. 2007 Jul;17(7):969-81.
doi: 10.1101/gr.6093907. Epub 2007 May 10.

An analysis of the gene complement of a marsupial, Monodelphis domestica: evolution of lineage-specific genes and giant chromosomes

Leo Goodstadt  1 , Andreas Heger, Caleb Webber, Chris P Ponting
Affiliations

An analysis of the gene complement of a marsupial, Monodelphis domestica: evolution of lineage-specific genes and giant chromosomes

Leo Goodstadt et al. Genome Res. 2007 Jul.

Abstract

The newly sequenced genome of Monodelphis domestica not only provides the out-group necessary to better understand our own eutherian lineage, but it enables insights into the innovative biology of metatherians. Here, we compare Monodelphis with Homo sequences from alignments of single nucleotides, genes, and whole chromosomes. Using PhyOP, we have established orthologs in Homo for 82% (15,250) of Monodelphis gene predictions. Those with single orthologs in each species exhibited a high median synonymous substitution rate (d(S) = 1.02), thereby explaining the relative paucity of aligned regions outside of coding sequences. Orthology assignments were used to construct a synteny map that illustrates the considerable fragmentation of Monodelphis and Homo karyotypes since their therian last common ancestor. Fifteen percent of Monodelphis genes are predicted, from their low divergence at synonymous sites, to have been duplicated in the metatherian lineage. The majority of Monodelphis-specific genes possess predicted roles in chemosensation, reproduction, adaptation to specific diets, and immunity. Using alignments of Monodelphis genes to sequences from either Homo or Trichosurus vulpecula (an Australian marsupial), we show that metatherian X chromosomes have elevated silent substitution rates and high G+C contents in comparison with both metatherian autosomes and eutherian chromosomes. Each of these elevations is also a feature of subtelomeric chromosomal regions. We attribute these observations to high rates of female-specific recombination near the chromosomal ends and within the X chromosome, which act to sustain or increase G+C levels by biased gene conversion. In particular, we propose that the higher G+C content of the Monodelphis X chromosome is a direct consequence of its small size relative to the giant autosomes.

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Figures

Figure 1.
Figure 1.
Proportion of Monodelphis domestica genes with Homo orthologs. The majority (82%) of protein coding genes have PhyOP-predicted orthologs among human genes. The classes of orthology relationships are indicated by counts of Homo orthologs followed by Monodelphis. Thus, a one-to-many relationship refers to a single Homo gene that is orthologous to several Monodelphis-specific duplications. Many of the genes with no predicted orthology with a Homo gene are nevertheless closely related to one or more Monodelphis genes with a low dS, indicating that these are Monodelphis-specific duplications. These are labeled as “Orphaned inparalogues.” This class includes genuine biological losses in the eutherian or human lineage, as well as heuristic failures in the PhyOP-prediction pipeline. The latter are often related to errors in gene predictions in difficult cases where there are many adjacent tandem duplications, such as among KRAB-ZnF genes. Similarly, many of the Monodelphis genes which have no plausible candidate ortholog in the human genome (labeled “Orphans with only distant homologues in Homo”) are likely to involve problematic gene predictions. The Monodelphis genes in the “No homology” class do not have significant BLAST alignments (E < 10−5) covering the majority of the sequence (75% of the shorter of the pair of sequences, and involving more than 50 residues). Most of these appear to be fragmentary, chimeric, or erroneous gene predictions, or noncoding sequence.
Figure 2.
Figure 2.
Oxford Grid (Edwards 1991) of PhyOP orthologs showing Homo–Monodelphis synteny blocks. (A) Genomic Synteny for all Monodelphis and Homo chromosomes. Genes are plotted in consecutive gene order along the Monodelphis chromosomes MDO1-8 and MDOX, and along the Homo chromosomes HSA1-22 and HSAX. One-to-one, one-to-many, many-to-one, and many-to-many Homo-to-Monodelphis orthologs are displayed as red, green, blue, and black dots, respectively. Diagonal lines represent genomic segments with conserved synteny. (B) The syntenic relationships for the ancient region of the Homo X chromosome that is syntenic to the Monodelphis X chromosome, and the more recently derived regions on the short arm of HSAX that are syntenic to MDO4 and MOD7. The circled regions have been placed on MDO4 and MDO7 in the current Monodelphis assembly 3, but FISH analyses map these regions to the Xq arm of MDOX (M. Breen and P. Water, pers. comm.).
Figure 3.
Figure 3.
G+C Content at 4D sites (GC4D) and dS in the Monodelphis and Homo X chromosomes. (A) GC4D values of Monodelphis genes in 1:1 orthology relationships with Homo genes. The cumulative distribution of GC4D for orthologs on the Monodelphis X chromosome is shifted to higher values compared with that for orthologs on Monodelphis autosomes, and genes on the Monodelphis X chromosome have a much increased median GC4D. This is exactly the opposite of the situation among Homo orthologs, where X chromosome genes have reduced GC4D. (B) The increased GC4D on the Monodelphis X chromosome is accompanied by an increase in median dS and a rightward shift of the dS cumulative distribution. This effect is even more pronounced when comparing orthologs between Monodelphis and Trichosurus, suggesting that much of the increase in dS has taken place along the marsupial lineage. (C) The dS for Homo–Monodelphis orthologs that lie on the Homo X chromosome and that are syntenic to the Monodelphis chromosome X or to chromosomes 4 and 7. Among orthologs on the Homo X chromosome, only those that are also found on the Monodelphis X chromosome have elevated dS, confirming that this is largely a marsupial-specific phenomenon.
Figure 4.
Figure 4.
G+C content along the Monodelphis X chromosome. This plot shows the increase in G+C content at the telomeric end of the long arm of the Monodelphis X chromosome. The thin blue lines show the G+C content for adjacent 50-kbp windows along MDOX, while the thick red line is a running average of 50 such windows. The average G+C content for the entire chromosome is shown by the horizontal green line.
Figure 5.
Figure 5.
dN, dS, dN/dS, and intron length vary with G+C content at 4D sites among Monodelphis–Homo and Monodelphis–Trichosurus 1:1 orthologs. (A,C) The variation of the median values for dN, dS, dN/dS, and Monodelphis intron lengths in Monodelphis–Homo 1:1 orthologs. (B,D) The same relationships for 1:1 orthologs between the two marsupials Monodelphis and Trichosurus. The orthologs were divided into five equally populated classes according to Monodelphis G+C content at 4D sites (GC4D). We found that median dN/dS dropped from 0.12 for Trichosurus orthologs and 0.11 for Homo orthologs in the lowest G+C class (G+C <31.5% and <34.5%, respectively) to a median dN/dS of 0.10 and 0.058 in the highest G+C class (G+C >56.1% and >63.5%, respectively). The higher median dN/dS values for orthologs from the two marsupial species is likely to stem, in part, from Trichosurus EST sequencing errors that disproportionately affect dN over dS. Genes with high GC4D also exhibit higher median dS and dN values and have reduced intron lengths.
Figure 6.
Figure 6.
Inferred rates of duplication for Monodelphis inparalogs among different functional categories. The timing of duplication events for Monodelphis-specific inparalogs were inferred from the dS-based rooted phylogenetic tree, and thus appears on a scale of dS/2 units. Although dS values vary substantially among genes (Fig. 3B), on average, a dS/2 value of 0.25 represents ∼90 million years. Genes in most functional classes (including olfaction, reproduction, detoxification, and immunity) follow a profile typical of other mammals with duplications peaking very recently. This would be in accordance with a rapid gene birth and death model. It is likely that reduction in the number of most recent duplications (dS/2 < 0.02) is due partly to the collapse of nearly identical sequence in the assembly, and partly to underprediction of sequence-similar adjacent paralogs and overestimation of very small dS values. The duplications of KRAB-ZnF genes are prominent in peaking at dS/2 ∼ 0.14.
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